Associations Among Tremor Amplitude, Activities of Daily Living, and Quality of Life in Patients with Essential Tremor

Background: Essential tremor (ET) is a disabling syndrome consisting of tremor, primarily in the upper limbs. We assessed the correlation of The Essential Tremor Rating Assessment Scale (TETRAS) Performance Item 4 ratings of upper limb tremor with the TETRAS activities of daily living (ADL) subscale and with 2 quality of life (QoL) scales. Methods: This noninterventional, cross-sectional, point-in-time survey of neurologists(n = 60), primary care physicians (n = 38), and their patients with ET (n = 1,003) used real-world data collected through the Adelphi ET Disease Specific Programme™. Physician-reported measures (TETRAS Performance Item 4 and TETRAS ADL total) and patient-reported QoL measures (generic EuroQol-5 Dimension 5 Level [EQ-5D-5 L] and ET-specific Quality of Life in Essential Tremor Questionnaire (QUEST)) were assessed with bivariate and multivariable analyses. Sensitivity analyses were also conducted. Results: The bivariate association between TETRAS Performance Item 4 score and TETRAS ADL total score was high (Pearson r = 0.761, P < 0.001). The bivariate associations between TETRAS Performance Item 4 score and EQ-5D-5 L index score (r = –0.410, P < 0.001) and between TETRAS ADL total score and EQ-5D-5 L index score (r = –0.543, P < 0.001) were moderate. The bivariate associations between TETRAS Performance Item 4 score and QUEST total score (r = 0.457, P < 0.001), and between TETRAS ADL total score and QUEST total score (r = 0.630, P < 0.001) were also moderate. These associations were unaltered by the inclusion of covariates. Discussion: This study showed that greater tremor severity (TETRAS Performance Item 4) was positively correlated with ADL impairment (TETRAS ADL) and negatively associated with QoL (EQ-5D-5 L and QUEST). TETRAS Performance Item 4 score is a robust predictor of TETRAS ADL total score, and TETRAS Performance Item 4 and TETRAS ADL total scores were robust predictors of the 2 QoL scales. The results demonstrate the value of TETRAS scores as valid endpoints for future clinical trials. Highlights This real-world study assessed TETRAS scores as predictors of impaired QoL in ET. TETRAS Performance Item 4 and ADL were associated with EQ-5D-5 L and QUEST. TETRAS scores may serve as valid endpoints for future clinical trials.


Association between upper limb tremor and ADL impairment
For core regression models, four patient-level covariates identified based on clinician inputs included age, an indicator for current diagnosis of depression, an indicator for current diagnosis of anxiety, and an indicator for current diagnosis of comorbidity potentially affecting movement/balance (patients were assigned a -1‖ if they had a diagnosis of Parkinson's disease, cerebrovascular disease, hemiplegia/paraplegia, or dementia, and a -0‖ if they did not have a diagnosis for one of these conditions).Clinicians hypothesized that higher age would be associated with greater impairment in everyday activities considered in TETRAS ADL.Diagnoses of anxiety and depression were included to account for potential differences in patients' self-assessment of tremor-related impairment, as well as the ADL-scale component directly related to tremor-related anxiety and embarrassment.Finally, clinicians indicated that comorbidities affecting movement and balance could lead to additional impairment in ADL.

Association between upper limb tremor or ADL and QoL
For core regression models, five patient-level covariates identified based on clinician inputs included age, an indicator for current diagnosis of depression, an indicator for current diagnosis of anxiety, CCI, and BMI.Clinicians expected that all included covariates in the core model had the potential to correlate with worse QoL.

Sensitivity model specifications
The sensitivity analyses incorporated additional variables including sex, treatment status (currently treated, previously treated, never treated), alcohol use to alleviate tremor symptoms (across 6 frequency categories), body mass index (BMI), and Charlson Comorbidity Index (CCI).Indicators of treatment status and alcohol use to alleviate tremor symptoms were incorporated due to their potential impact on symptoms (or perception of symptoms), as well as the possibility that treatment could be prescribed more often to patients with greater ADL impairment (across varying levels of ET tremor amplitude).Inclusion of BMI was intended to account for potential movement difficulties stemming from obesity, while sex was added as an additional demographic control.CCI was included to control for impact on TETRAS ADL impairment scores related to a patient's overall comorbidity profile.For regressions with EQ-5D index score as the dependent variable, a two-part generalized linear modelling (GLM) framework was also considered (recommended by ISPOR for EQ-5D-related regression analysis).Two-part models first estimate the probability (using a probit model) that the EQ-5D decrement (1 minus the EQ-5D score) is 0 (equivalent to an EQ-5D score of 1 prior to transformation) and subsequently fit a GLM (assuming a gamma distribution of errors and a log link function) to estimate the magnitude of EQ-5D decrements in the case where the score is not at the boundary.
For regressions with QUEST total score as the dependent variable, models assuming a gamma distribution of responses were also estimated.

Upper limb tremor and ADL
Expanded model results with additional regression covariates (sex, treatment status, alcohol use to alleviate tremor symptoms, BMI, and CCI) demonstrated an association between TETRAS Performance Item 4 score and TETRAS ADL Total score (Supplementary Table 3), similar to the core regression model.A 1-point higher TETRAS Performance Item 4 score was associated with a 1.38-point higher mean TETRAS ADL Total score (P<0.01).The covariates of female sex and patients currently treated for ET were significantly associated with increased ADL Total score (both, P<0.01) (Supplementary Table 3).Core multivariable model results with physician-level RE were similar to core results with physician-level FE in the random intercept models (Supplementary Table 3).

Upper limb tremor and generic QoL
Expanded model results with additional regression covariates (sex, household income, an indicator for moderate-to-severe treatment-related adverse effects) demonstrated an association between TETRAS Performance Item 4 score and EQ-5D-5L Index score (Supplementary Table 5), similar to the core regression model.A 1-point higher TETRAS Performance Item 4 score was associated with a 0.0143-point lower mean EQ-5D-5L Index score (P<0.01).The covariate of moderate-to-severe treatment-related adverse effects was significantly associated with EQ-5D Index score (P<0.05)(Supplementary Table 5).Estimates from the two-part model for core and expanded multivariable regression models were comparable to those estimated using the linear model (Supplementary Table 5).

ADL and generic QoL
Expanded model results with additional regression covariates (sex, household income, an indicator for moderate-to-severe treatment-related adverse effects) demonstrated an association between TETRAS ADL Total score and EQ-5D-5L Index score (Supplementary Table 6), similar to the core regression model.A 1-point higher TETRAS ADL Total score was associated with a 0.0098-point lower mean EQ-5D-5L Index score (P<0.01).Estimates from the two-part model for TETRAS ADL were comparable to those estimated using the linear model (Supplementary Table 6).

Upper limb tremor and ET-specific QoL
Expanded model results with additional regression covariates (sex, household income, an indicator for moderate-to-severe treatment-related adverse effects) demonstrated an association between TETRAS Performance Item 4 score and QUEST Total score (Supplementary Table 7), similar to the core regression model.A 1-point higher TETRAS Performance Item 4 score was associated with a 1.652-point higher mean QUEST Total score (P<0.01).The covariates of patient-reported moderate-to-severe treatment-related adverse events (P<0.01) and household income in the $50k to $100k range (P<0.05) were significantly associated with increased QUEST Total score (Supplementary Table 7).

ADL and ET-specific QoL
Expanded model results with additional regression covariates (sex, household income, an indicator for moderate-to-severe treatment-related adverse effects) demonstrated an association between TETRAS ADL Total score and QUEST Total score (Supplementary Table 8), similar to the core regression model.A 1-point higher TETRAS ADL Total score was associated with a 1.149-point higher mean QUEST Total score (P<0.01).Supplementary Table 1

. Demographic and clinical characteristics of the study population
Table reports patient characteristics for all patients with data derived from standardized clinician reports in the Adelphi ET DSP TM (N=1,003).2. Table reports patient characteristics for all patients with data derived from patient-reported surveys in the Adelphi ET DSP TM with a nonmissing EQ-5D-5L Index score (N=463).3. Table reports patient characteristics for all patients with data derived from patient-reported surveys in the Adelphi ET DSP TM with a nonmissing QUEST Total score (N=456).4. In instances where responses differed between the standardized clinician reports and patient-reported surveys, responses from patient-reported questionnaires were utilized.

Bivariate analyses for the associations of TETRAS ADL total score with TETRAS Performance Item 4 score and patient-level covariates
Key dependent and independent variables for bivariate analyses were based on review of survey questions and guidance from two clinicians with specialization in movement disorders.1.For variables with continuous data, Pearson correlation tests were conducted to measure the strength of the linear relationship with primary outcome variables.2. For variables with binary categorical data, Welch two-sample t-tests were conducted to test the null hypothesis that primary outcome means were equal across categories.3.For variables with multicategorical data, one-way ANOVA tests were conducted to test the null hypothesis that primary outcome means were equal across categories.
ADL, activities of daily living; ANOVA, analysis of variance; BMI, body mass index; CCI, Charlson comorbidity index; ET, essential tremor; TETRAS, The Essential Tremor Rating Assessment Scale.Supplementary Table3.

Expanded multivariable analyses for the associations of TETRAS ADL total score with TETRAS Performance Item 4 score and patient-level covariates
ADL, activities of daily living; BMI, body mass index; CCI, Charlson comorbidity index; ET, essential tremor; FE, fixed effects; RE, random effects; SE, standard error; TETRAS, The Essential Tremor Rating Assessment Scale.Supplementary Table 4.

Bivariate analyses for associations of EQ-5D-5L index score and QUEST total score with TETRAS Performance Item 4 score, ADL total score, and patient- level covariates
Key dependent and independent variables for bivariate analyses were based on review of survey questions and guidance from two clinicians with specialization in movement disorders.1.For variables with continuous data, Pearson correlation tests were conducted to measure the strength of the linear relationship with primary outcome variables.2. For variables with binary categorical data, Welch two-sample t-tests were conducted to test the null hypothesis that primary outcome means were equal across categories.3.For variables with multicategory data, one-way ANOVA tests were conducted to test the null hypothesis that primary outcome means were equal across categories.ADL, activities of daily living; ANOVA, analysis of variance; BMI, body mass index; CCI, Charlson comorbidity index; EQ-5D-5L, EuroQol-5 Dimension 5 Level; QUEST, Quality of Life in Essential Tremor questionnaire; TETRAS, The Essential Tremor Rating Assessment Scale.

Table 7 . Expanded multivariable analyses for the associations of QUEST total score with TETRAS Performance Item 4 score and patient-level covariates
**P<0.01, **P<0.05.BMI, body mass index; CCI, Charlson comorbidity index; OLS, ordinary least squares; QUEST, Quality of Life in Essential Tremor questionnaire; SE, standard error; TETRAS, The Essential Tremor Rating Assessment Scale. *

Table 8 . Expanded multivariable analyses for the associations of QUEST total score with TETRAS ADL total score and patient-level covariates
**P<0.01, **P<0.05.ADL, activities of daily living; BMI, body mass index; CCI, Charlson comorbidity index; OLS, ordinary least squares; QUEST, Quality of Life in Essential Tremor questionnaire; SE, standard error; TETRAS, The Essential Tremor Rating Assessment Scale. *